P576: A PHASE I/II STUDY OF MILADEMETAN (DS3032B) IN COMBINATION WITH LOW DOSE CYTARABINE WITH OR WITHOUT VENETOCLAX IN ACUTE MYELOID LEUKEMIA
Authors: J. Senapati, J. Ishizawa, H. A. Abbas, S. Loghavi, G. Borthakur, G. C. Issa, S. I. Dara, R. Pourebrahim, N. Daver, E. J. Jabbour, S. M. Kornblau, N. Pemmaraju, G. Garcia-Manero, F. Ravandi, M. Muftuoglu, J. Khoury, C. DiNardo, M. Andreeff
Journal: HemaSphere (2022)

Background: In TP53 wild type (WT) acute myeloid leukemia (AML), inhibition of MDM2 increases p53 protein expression and mediates antileukemic effects. MDM2i monotherapy in AML has shown only modest responses; combining MDM2i with anti-leukemic therapies with additive or synergistic pre-clinical activity and non-overlapping toxicities might potentiate therapeutic benefit. Aims: To evaluate safety and efficacy of milademetan (DS-3032b), an MDM2i, with low dose cytarabine (LDAC) ± venetoclax (VEN) in patients (pts) with AML. Methods: This open label, single arm Phase I/II trial (NCT03634228) included pts with AML and WT TP53. The phase I utilized a 3 + 3 design to identify safety and tolerability of the combination and determine the recommended combination dose to proceed to the expansion phase (phase II). Pts included were adult (≥18 years), ECOG PS ≤ 3, with adequate renal and hepatic function. Key exclusion criteria included acute promyelocytic leukemia, prior therapy with MDM2i, or stem cell transplantation (SCT) in the preceding 60 days. Doses of milademetan and combination therapy are provided in Table 1. Toxicity was graded according to the NCI-CTCAE v.5 and responses according to the ELN 2017 AML response criteria. Results: A total of 21 pts were screened; 16 pts were enrolled and treated in phase I. Median age was 70 years (range, 23-80) and 11 (69%) were women. Median number of prior therapies was 3 (range, 1-7), with 6 pts (37%) who had undergone prior SCT. Two pts (12.5%) were newly diagnosed with treated secondary AML; having received 3 and 2 lines of therapy for prior MDS. Milademetan combination therapy was reasonably well tolerated at all dose levels, the most common adverse events being gastrointestinal. One pt had an attributable grade 3-4 toxicity (diarrhea), which was considered a dose limiting toxicity. Pts received a median of 1 cycle (range, 1-4). Two pts (12.5%) achieved an overall response (CRp, 12.5%, 1 each at dose level 1 and 2). At a median follow up of 10.5 mos (range, 0.6-17), 5 pts are alive (31%), all on subsequent lines of therapy. Ten of 11 deaths occurred in non-responding pts and were attributed to disease progression or infection. One responding pt died of infection in cycle 3. Given the minimal response rates at all dose levels, the phase II expansion portion of the trial was not conducted. p53 immunohistochemistry was performed on baseline bone marrow (BM) samples from 11 pts, all of whom had WT expression pattern. BM samples of 1 amongst 7 pts evaluated post C1 demonstrated acquisition of mutant p53. We performed CyTOF analysis of sequentially collected samples to interrogate signalling pathways, the p53-MDM2 axis, and the abundance of pro/anti-apoptotic molecules. We observed that CD34+ leukemia blasts expressed high levels of Bcl-2 and were eliminated after therapy in a patient with CRp while Bcl-2 low non-malignant monocytic cells preferentially enriched. Comparative single-cell proteomic analysis in responders and non-responders are underway to identify proteomic correlates of favourable response vs. therapy resistance. Image:Summary/Conclusion: The combination of milademetan with LDAC ± venetoclax was reasonably well tolerated but showed only minimal clinical responses at all 3 dose levels in a heavily pre-treated AML population. Further studies are needed to decipher the most appropriate combination regimen and pt population to benefit from milademetan.